Mice deficient for the STAT6 gene (STAT6−/− mice) have enhanced immunosurveillance against primary and metastatic tumors. Because STAT6 is a downstream effector of the IL-4R, and IL-13 binds to the type 2 IL-4R, IL-13 has been proposed as an inhibitor that blocks differentiation of tumor-specific CD8+ T cells. Immunity in STAT6−/− mice is unusually effective in that 45–80% of STAT6−/− mice with established, spontaneous metastatic 4T1 mammary carcinoma, whose primary tumors are surgically excised, survive indefinitely, as compared with< 10% of STAT+/+(BALB/c) mice. Surprisingly, STAT6−/− and BALB/c reciprocal bone marrow chimeras do not have increased immunosurveillance, demonstrating that immunity requires STAT6−/− hemopoietic and nonhemopoietic components. Likewise, CD1−/− mice that are NKT deficient and therefore IL-13 deficient also have heightened tumor immunity. However, STAT6−/− and CD1−/− reciprocal bone marrow chimeras do not have increased survival, suggesting that immunity in STAT6−/− and CD1−/− mice is via noncomplementing mechanisms. Metastatic disease is not reduced in BALB/c mice treated with an IL-13 inhibitor, indicating that IL-13 alone is insufficient for negative regulation of 4T1 immunity. Likewise, in vivo depletion of CD4+ CD25+ T cells in BALB/c mice does not increase survival, demonstrating that CD4+ CD25+ cells do not regulate immunity. Cytokine production and tumor challenges into STAT6−/− IFN-γ−/− mice indicate that IFN-γ is essential for immunity. Therefore, immunosurveillance in STAT6−/− mice facilitates survival against metastatic cancer via an IFN-γ-dependent mechanism involving hemopoietic and nonhemopoietic derived cells, and is not exclusively dependent on counteracting IL-13 or CD4+ CD25+ T cells.